Alzheimer's disease (AD) is a devastating chronic and progressive neurological disorder that affects more than 37 million people worldwide (Mount, C. and Downton, C. Nature Med. 2006, 12, 780-784). It is clinically characterized by progressive cognitive impairments or decline defined by a loss of memory and learning ability, together with a reduced ability to perform daily routine activities and a diverse array of neuropsychiatric symptoms such as apathy, verbal and physical agitation, irritability, anxiety, depression, delusions and hallucinations. Two forms of AD exist: a familial one (multiple family members are affected) and a sporadic one, in which one or a few members of a family develop the disease. The number of AD affected persons is expected to triple or quadruple by 2050 and expected to become the developed world's largest socioeconomic healthcare burden over the coming decades (Mount, C. and Downton, C. Nature Med. 2006, 12, 780-784). Characteristic neuropathologic findings include selective neuronal and synaptic losses, extracellular neuritic plaques containing the β-amyloid peptide and neurofibrillary tangles (NFTs) composed of hyperphosphorylated forms of the tau (τ) protein (Klafki, H. W. et al. Brain 2006, 129, 2840-2855). Current medications that have passed FDA approval for the treatment of Alzheimer's disease include acetylcholinesterase (AChE) inhibitors, namely, Tacrine, Rivastigmine, Donepezil, and Galantamine for mild to moderate cases, and N-methyl-D-aspartate (NMDA)-receptor antagonist memantine for the treatment of moderate to severe Alzheimer's disease.
Apart from above mentioned drugs, extensive efforts toward the novel cholinesterase inhibitors have led to few more potent compounds such as Xanthostigmine, Physostigmine, Phenserine, Huperzine-A, Bis-tacrine, Bis-huperzin-B, Quilostigmine, Eptastigmine, Ro-46-5934, P10358, CHF2819 etc. Apart from this, some pyridinium or quinolinium carbamate derivatives have been disclosed as AChE inhibitors in US2009/0062279, in WO97/08146. Nevertheless, these compounds present the drawback of being unstable in vivo and very rapidly deactivated.
In the recent past, we have disclosed substituted carbamic acid quinolin-6-yl esters as orally effective AChE inhibitors in WO2006/070394; in US2006/0142335; and in Chaudhary, S. S. et al. J. Med. Chem. 2010, 53, 6490-6505.
Current drugs for Alzheimer's disease, namely, tacrine, donepezil, rivastigmine, galanthamine and memantine are not able to alter or prevent disease progression and suffer from major drawback of loss of therapeutic potential with time. They are, instead, palliative in alleviating disease symptoms (Melnikova, I. Nat. Rev. Drug Discovery 2007, 6, 341-342). Thus, increasing daily doses in such circumstances increases the side effects until the pause of the treatment. The major side effects are specifically caused by the peripheral activity of these drugs on cholinesterase enzyme.
As the average age is increasing all over the world, and so the AD (66% in the developing countries), there is an urgent need for novel therapeutics which could act as anti-Alzheimer agents with low or no side effects associated with the known commercial drugs for the treatment of Alzheimer's disease. Specifically, there is a need for new cholinesterase inhibitors with wider therapeutic window, to be useful as potential anti-Alzheimer agents without interacting with peripheral cholinesterase enzyme.